This project will initate research, the long-term goals of which are to determine whether absorption of chemicals across human skin changes with age and to identify the biological and physiological reasons for this dependence. The pilot study proposed will take the first exploratory steps to answer these questions by comparing the percutaneous penetration rate and extent of a series of compounds of different physiocochemical characteristics in a group of young human subjects (18-30 years) with that in two elderly cohorts (65-75 yrs and greater than 75 yrs). The investigation is important and of clinical relevance because of the recent and increasing trend towards the use of transdermal drug delivery for systemic effect and because more people of advanced years than ever before are applying medicaments topically for chemotherapeutic purposes. Current knowledge in this area is sparse and inconclusive; despite much research into the biology of skin aging, the possible alterations in cutaneous barrier function have not been identified and are not intuitively obvious. Percutaneous absorption will be measured in vivo in young and old subject populations; a number of "model" penetrants (including hydrocortisone, testosterone and estradiol; urea, butanol and caffeine; and benzoic, salicylic and acetylsalicylic acids) will be studied. 14C-labeled compounds will be administered topically, and absorption will be determined from urinary excretion rate data and from local activity disappearance kinetics. Pharmacokinetic analysis will be performed classically and with a novel, physical model which is sensitive to the biophysicochemical interactions between penetrant and skin. In this way, for a wide range of penetrant molecules, differences in percutaneous absorption between subject populations of disparate ages (young vs. old) will be identified. The study will therefore begin to answer the following questions. Are there differences? How great are the differences? Are molecules of different physical chemistry affected in the same way? Are there indications of how observed differences can be related to known biological changes? At this point, it is believed, the research will have reached a stage from which a larger and more detailed investigation may be planned and implemented to attain the stated long-term goals.